Nasal formulations of metoclopramide

ABSTRACT

Nasal formulations of metoclopramide, which remain stable and/or colorless upon storage over a period of time, are provided. Also provided are methods of treating disorders treatable with metoclopramide, comprising administering the nasal solutions to patients in need thereof.

This application is a continuation of U.S. patent application Ser. No.15/130,086, filed Apr. 15, 2016, which is a continuation of U.S. patentapplication Ser. No. 13/660,709, filed Oct. 25, 2012, which is acontinuation of U.S. patent application Ser. No. 12/645,108, filed Dec.22, 2009, which claims the benefit of U.S. Provisional Patent No.61/140,034, filed Dec. 22, 2008, each of which application isincorporated herein in its entirety by reference.

BACKGROUND OF THE INVENTION

Metoclopramide is approved in the United States in oral solution, oraltablet and injectable solution forms. Wenig has suggested the use ofnasally-administered metoclopramide for the treatment of emesis ornausea. (See U.S. Pat. No. 4,624,965, issued Nov. 25, 1986, which isincorporated by reference herein in its entirety.) Psilogenis hassuggested nasal administration of metoclopramide for the treatment ofdelayed onset emesis. (See U.S. Pat. No. 5,760,086, issued Jun. 2, 1998,incorporated herein by reference in its entirety.) Lehman et al. haveproposed administering nasal formulations of metoclopramide for thetreatment of gastroparesis. (See U.S. Pat. No. 6,770,262, issued Aug. 3,2004, incorporated herein by reference in its entirety.)

SUMMARY OF THE INVENTION

The inventors have discovered that, though previously-described nasalsolutions of metoclopramide are substantially free of color or colorlesswhen initially formulated, they tend to become discolored on storage. Inparticular, the inventors have determined that under acceleratedstability conditions, which are designed to simulate long-term storageconditions typical for nasal solutions, the previously-described nasalsolutions of metoclopramide tend to take on a yellow-to-brown color.Accordingly, the inventors have determined that there is a need for annasal solution of metoclopramide that is stable over time. The inventorshave also determined that there is a need for an nasal solution ofmetoclopramide that is substantially free of color when formulated, andthat remains substantially free of color over time. Accordingly, thepresent disclosure concerns pharmaceutical compositions for nasaladministration that are stable upon long-term storage, that remainsubstantially free of color, and/or that remain substantially clear uponlong-term storage. Further characteristics, uses and advantages of theinvention will become clear to the person having skill in the art uponconsideration of the following disclosure.

Some embodiments described herein provide a pharmaceutical compositioncomprising metoclopramide, or a pharmaceutically-acceptable saltthereof, a citrate buffer, and benzalkonium chloride; wherein thecomposition is stable; and wherein the composition has a citrateconcentration ([citrate]=[citric acid]+[dihydrogen citrateion]+[hydrogen citrate ion]+[citrate ion]) of at least about 10millimolar.

Some embodiments described herein provide a pharmaceutical compositioncomprising metoclopramide, or a pharmaceutically-acceptable saltthereof, a citrate buffer, and benzalkonium chloride; wherein thecomposition is substantially free of color; and wherein the compositionhas a citrate concentration ([citrate]=[citric acid]+[dihydrogen citrateion]+[hydrogen citrate ion]+[citrate ion]) of at least about 10millimolar.

Some embodiments described herein provide a pharmaceutical compositioncomprising metoclopramide, or a pharmaceutically-acceptable saltthereof, a citrate buffer, and benzalkonium chloride; wherein thecomposition is substantially clear; and wherein the composition has acitrate concentration ([citrate]=[citric acid]+[dihydrogen citrateion]+[hydrogen citrate ion]+[citrate ion]) of at least about 10millimolar.

Some embodiments described herein provide a pharmaceutical compositioncomprising metoclopramide, or a pharmaceutically-acceptable saltthereof, a buffer, and benzalkonium chloride; wherein the composition isstable; and wherein the composition has a pH of above about 4.5.

Some embodiments described herein provide a pharmaceutical compositioncomprising metoclopramide, or a pharmaceutically-acceptable saltthereof, a citrate buffer, and benzalkonium chloride; wherein thecomposition is substantially free of color; and wherein the compositionhas a pH of above about 4.5.

Some embodiments described herein provide a pharmaceutical compositioncomprising metoclopramide, or a pharmaceutically-acceptable saltthereof, a citrate buffer, and benzalkonium chloride; wherein thecomposition is substantially clear; and wherein the composition has a pHof above about 4.5.

Some embodiments described herein provide a pharmaceutical compositioncomprising metoclopramide, or a pharmaceutically-acceptable saltthereof, a citrate buffer, and optionally less than about 1% w/v benzylalcohol; wherein the composition is stable; and wherein the compositionhas a citrate concentration ([citrate]=[citric acid]+[dihydrogen citrateion]+[hydrogen citrate ion]+[citrate ion]) of at least about 10millimolar. In some embodiments, the composition comprises about 0.75%w/v benzyl alcohol or less, or about 0.5% w/v benzyl alcohol or less.

Some embodiments described herein provide a pharmaceutical compositioncomprising metoclopramide, or a pharmaceutically-acceptable saltthereof, a citrate buffer, and optionally less than about 1% w/v benzylalcohol; wherein the composition is free of color; and wherein thecomposition has a citrate concentration ([citrate]=[citricacid]+[dihydrogen citrate ion]+[hydrogen citrate ion]+[citrate ion]) ofat least about 10 millimolar. In some embodiments, the compositioncomprises about 0.75% w/v benzyl alcohol or less, or about 0.5% w/vbenzyl alcohol or less.

Some embodiments described herein provide a pharmaceutical compositioncomprising metoclopramide, or a pharmaceutically-acceptable saltthereof, a citrate buffer, and optionally less than about 1% w/v benzylalcohol; wherein the composition is substantially clear; and wherein thecomposition has a citrate concentration ([citrate]=[citricacid]+[dihydrogen citrate ion]+[hydrogen citrate ion]+[citrate ion]) ofat least about 10 millimolar. In some embodiments, the compositioncomprises about 0.75% w/v benzyl alcohol or less, or about 0.5% w/vbenzyl alcohol or less.

Some embodiments described herein provide for use of a metoclopramidesolution as described herein, for preparation of a medicament for thetreatment of a disorder that is treatable with metoclopramide.

Some embodiments described herein provide a manufacture comprising ametoclopramide pharmaceutical composition as described herein, and ameans for nasal administration of said composition to a patient.

Additional embodiments, features and advantages will become apparentupon consideration of the following detailed description of theinvention.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed toward nasally-administrable solutionscomprising metoclopramide, which are stable upon storage, especiallylong-term storage. The invention is further directed towardnasally-administrable metoclopramide solutions, which are clear and/orcolorless. The invention is further directed towardnasally-administrable metoclopramide solutions, which are clear and/orcolorless when initially formulated (compounded) especially after filledin pharmaceutical device glass containers, and which remainsubstantially clear and/or colorless upon storage, e.g. upon long-termstorage. Substantial clarity and colorlessness may be evaluated by oneof the methods described herein.

The inventors are believed to be the first to provide a practicalsolution to the problem of eventual discoloration ofpreviously-described nasal metoclopramide compositions. Thepreviously-described nasal metoclopramide solutions tend to becomediscolored upon storage, even when they are clear as initiallyformulated. This tendency is especially pronounced when thepreviously-described nasal metoclopramide solutions are subjected toaccelerated conditions from about 25° C. to 40° C. or higher, e.g. at40° C./75% RH (“RH” being relative humidity). While it is not known atthis time what causes the previously-known nasal formulations ofmetoclopramide to become discolored upon storage, especially underaccelerated conditions, it is considered undesirable for a solution thatis clear and colorless when originally formulated to become colored uponstorage. Given the scrutiny applied to pharmaceutical compositions bypharmaceutical industry regulatory bodies, it is considered necessary toreduce or eliminate discoloration of pharmaceutical compositions if atall possible, at least over the period of time during which, and underthe conditions at which, they are likely to be stored. In order toincrease patient acceptance of metoclopramide solutions, the presentinventors increased the pH of previous metoclopramide solutions closerto neutral, only to find that the increase in pH led to increaseddiscoloration of the metoclopramide solutions. In addition toidentifying the problem of increased discoloration upon storage ofhigher pH formulations of previously-described solutions ofmetoclopramide, the inventors are also the first to have provided asolution to the problem of discoloration. Factors that can affectstability of aqueous solutions of metoclopramide include the specificbuffer, the pH of the buffered solution, and the presence or absence ofbenzyl alcohol and/or benzalkonium chloride. An additional factor indiscoloration of metoclopramide solutions is exposure of the solution tolight, especially during long-term storage.

Thus, in some embodiments described herein there is provided apharmaceutical composition comprising metoclopramide (or apharmaceutically-acceptable salt thereof), citrate buffer andbenzalkonium chloride having a pH of at least about 5.

Some embodiments described herein provide a pharmaceutical compositioncomprising metoclopramide, or a pharmaceutically-acceptable saltthereof, a citrate buffer, and benzalkonium chloride; wherein thecomposition is stable; and wherein the composition has a citrateconcentration ([citrate]=[citric acid]+[dihydrogen citrateion]+[hydrogen citrate ion]+[citrate ion]) of at least about 10millimolar. Other embodiments described herein provide a pharmaceuticalcomposition comprising metoclopramide, or a pharmaceutically-acceptablesalt thereof, a citrate buffer, and benzalkonium chloride; wherein thecomposition is substantially free of color; and wherein the compositionhas a citrate concentration ([citrate]=[citric acid]+[dihydrogen citrateion]+[hydrogen citrate ion]+[citrate ion]) of at least about 10millimolar. Other embodiments described herein provide a pharmaceuticalcomposition comprising metoclopramide, or a pharmaceutically-acceptablesalt thereof, a citrate buffer, and benzalkonium chloride; wherein thecomposition is substantially clear; and wherein the composition has acitrate concentration ([citrate]=[citric acid]+[dihydrogen citrateion]+[hydrogen citrate ion]+[citrate ion]) of at least about 10millimolar. In some embodiments, the composition has a citrateconcentration ([citrate]=[citric acid]+[dihydrogen citrateion]+[hydrogen citrate ion]+[citrate ion]) of at least about 10millimolar, at least about 15 millimolar, at least about 20 millimolar,about 10-100 millimolar, about 10-50 millimolar, about 10-25 millimolar,about 10-20 millimolar, about 10-15 millimolar, about 15-100 millimolar,about 15-50 millimolar, about 15-25 millimolar or about 15-20millimolar. In some embodiments, the pharmaceutical composition has astarting pH of at least about 4.5, at least about 4.6, at least about4.7, at least about 4.8, at least about 4.9, at least about 5.0, atleast about 5.1 or at least about 5.2, in a range of about 4.5-6.0, in arange of about 4.6-5.9, in a range of about 4.7-5.8, in a range of about4.8-5.7, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6,about 5.7, about 5.8, about 5.9 or about 6.0. In some embodiments, thecomposition is substantially free of any additional antioxidant. In someembodiments, the composition further comprises at least one member ofthe group consisting of a salt, EDTA, sorbitol, a sugar (including areduced sugar, such as sorbitol) or a flavoring agent. In someembodiments, the pharmaceutical composition has a concentration ofmetoclopramide, or a pharmaceutically-acceptable salt thereof, of fromabout 20.0% (w/v) to about 30.0% (w/v). In some embodiments, thepharmaceutical composition has a concentration of benzalkonium chloridefrom about 0.005% (w/v) to about 0.05% (w/v). In some embodiments, thepharmaceutical composition has an osmolality of from about 500 mOsm/kgto about 1400 mOsm/kg. In some embodiments, the osmolality is from about500 mOsm/kg to about 1000 mOsm/kg. In some embodiments, the osmolalityis from about 1000 mOsm/kg to about 1400 mOsm/kg. In some embodiments,the composition remains stable on storage at a temperature of about 25°C. to about 40° C. for at least about 4 weeks, at least about 6 weeks,at least about 8 weeks, at least about 10 weeks, at least about 12weeks, at least about 16 weeks, at least about 20 weeks or at leastabout 6 months. In some embodiments, the composition remainssubstantially free of color on storage at a temperature of about 25° C.to about 40° C. for at least about 4 weeks, at least about 6 weeks, atleast about 8 weeks, at least about 10 weeks, at least about 12 weeks,at least about 16 weeks, at least about 20 weeks or at least about 6months. In some embodiments, the composition remains substantially clearon storage at a temperature of about 25° C. to about 40° C. for at leastabout 4 weeks, at least about 6 weeks, at least about 8 weeks, at leastabout 10 weeks, at least about 12 weeks., at least about 16 weeks, atleast about 20 weeks or at least about 6 months.

Some embodiments described herein provide a pharmaceutical compositioncomprising metoclopramide, or a pharmaceutically-acceptable saltthereof, a buffer, and benzalkonium chloride; wherein the composition isstable; and wherein the composition has a pH of above about 4.5. Someembodiments described herein provide a pharmaceutical compositioncomprising metoclopramide, or a pharmaceutically-acceptable saltthereof, a citrate buffer, and benzalkonium chloride; wherein thecomposition is substantially free of color; and wherein the compositionhas a pH of above about 4.5. Some embodiments described herein provide apharmaceutical composition comprising metoclopramide, or apharmaceutically-acceptable salt thereof, a citrate buffer, andbenzalkonium chloride; wherein the composition is substantially clear;and wherein the composition has a pH of above about 4.5. In someembodiments, the pharmaceutical composition has a starting pH of atleast about 4.6, at least about 4.7, at least about 4.8, at least about4.9, at least about 5.0, at least about 5.1 or at least about 5.2, in arange of about 4.5-6.0, in a range of about 4.6-5.9, in a range of about4.7-5.8, in a range of about 4.8-5.7, about 4.5, about 4.6, about 4.7,about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9 or about 6.0.In some embodiments, the composition remains stable on storage at atemperature of about 25° C. to about 40° C. for at least about 4 weeks,at least about 6 weeks, at least about 8 weeks, at least about 10 weeks,at least about 12 weeks, at least about 16 weeks, at least about 20weeks or at least about 6 months. In some embodiments, the compositionremains substantially free of color on storage at a temperature of about25° C. to about 40° C. for at least about 4 weeks, at least about 6weeks, at least about 8 weeks, at least about 10 weeks, at least about12 weeks, at least about 16 weeks, at least about 20 weeks or at leastabout 6 months. In some embodiments, the composition remainssubstantially clear on storage at a temperature of about 25° C. to about40° C. for at least about 4 weeks, at least about 6 weeks, at leastabout 8 weeks, at least about 10 weeks, at least about 12 weeks, atleast about 16 weeks, at least about 20 weeks or at least about 6months. In some embodiments, the buffer is selected from the groupconsisting of citric acid/phosphate, acetate, barbital, borate,Britton-Robinson, cacodylate, citrate, collidine, formate, maleate,McIlvaine, phosphate, Prideaux-Ward, succinate, citrate-phosphate-borate(Teorell-Stanhagen), veronal acetate, MES(2-(N-morpholino)ethane-sulfonic acid), BIS-TRIS(bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA(N-(2-acetamido)-2-iminodiacetic acid), ACES(N-(carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES(piperazine-N,N′-bis(2-ethanesulfonic acid)), MOPSO(3-(N-morpholino)-2-hydroxy-propanesulfonic acid), BIS-TRIS PROPANE(1,3-bis(tris(hydroxymethyl)methylamino)propane), BES(N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS(3-(N-morpholino)propane-sulfonic acid), TES(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), DIPSO(3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS(4-(N-morpholino)butanesulfonic acid), TAPSO(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxy-propanesulfonic acid),tris(hydroxymethylamino-methane, HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid), POPSO(piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)), TEA(triethanolamine), EPPS(N-(2-hydroxyethyl)piperazine-N′-(3-propane-sulfonic acid), TRICINE(N-tris(hydroxymethyl)methyl-glycine), GLY-GLY (glycylglycine), BICINE(N,N-bis(2-hydroxyethyl)glycine), HEPBS(N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid)), TAPS(N-tris(hydroxy-methyl)methyl-3-aminopropanesulfonic acid), or AMPD(2-amino-2-methyl-1,3-propanediol) buffer.

Some embodiments described herein provide a pharmaceutical compositioncomprising metoclopramide, or a pharmaceutically-acceptable saltthereof, and citric acid as a stabilizer, wherein the composition isstable. Some embodiment described herein provide a pharmaceuticalcomposition comprising metoclopramide, or a pharmaceutically-acceptablesalt thereof, and citric acid as a stabilizer, wherein the compositionis substantially free of color. Some embodiments described hereinprovide a pharmaceutical composition comprising metoclopramide, or apharmaceutically-acceptable salt thereof, and citric acid as astabilizer, wherein the composition is substantially clear. In someembodiments, the composition has a citric acid concentration of at leastabout 5 millimolar, at least about 10 millimolar, at least about 15millimolar, at least about 20 millimolar, about 5-100 millimolar, about5-50 millimolar, about 5-25 millimolar, about 5-20 millimolar, about5-15 millimolar, about 5-10 millimolar, about 10-100 millimolar, about10-50 millimolar, about 10-25 millimolar, about 10-20 millimolar, about10-15 millimolar, about 15-100 millimolar, about 15-50 millimolar, about15-25 millimolar or about 15-20 millimolar. In some embodiments, thecomposition is substantially free of any additional antioxidant. In someembodiments, the composition further comprises at least one member ofthe group consisting of a salt, EDTA, sorbitol, a sugar (including areduced sugar, such as sorbitol) or a flavoring agent. In someembodiments, the pharmaceutical composition has a concentration ofmetoclopramide, or a pharmaceutically-acceptable salt thereof, of fromabout 20.0% (w/v) to about 30.0% (w/v). In some embodiments, thecomposition further contains benzalkonium chloride at a concentrationfrom about 0.005% (w/v) to about 0.05% (w/v). In some embodiments, thepharmaceutical composition has an osmolality of from about 500 mOsm/kgto about 1400 mOsm/kg. In some embodiments, the osmolality is from about500 mOsm/kg to about 1000 mOsm/kg. In some embodiments, the osmolalityis from about 1000 mOsm/kg to about 1400 mOsm/kg. In some embodiments,the composition remains stable on storage at a temperature of about 25°C. to about 40° C. for at least about 4 weeks, at least about 6 weeks,at least about 8 weeks, at least about 10 weeks, at least about 12weeks, at least about 16 weeks, at least about 20 weeks or at leastabout 6 months. In some embodiments, the composition remainssubstantially free of color on storage at a temperature of about 25° C.to about 40° C. for at least about 4 weeks, at least about 6 weeks, atleast about 8 weeks, at least about 10 weeks, at least about 12 weeks,at least about 16 weeks, at least about 20 weeks or at least about 6months. In some embodiments, the composition remains substantially clearon storage at a temperature of about 25° C. to about 40° C. for at leastabout 4 weeks, at least about 6 weeks, at least about 8 weeks, at leastabout 10 weeks, at least about 12 weeks, at least about 16 weeks, atleast about 20 weeks or at least about 6 months.

Some embodiments described herein provide a pharmaceutical compositioncomprising metoclopramide, or a pharmaceutically-acceptable saltthereof, a citrate buffer, and optionally less than about 1% w/v benzylalcohol; wherein the composition is stable; and wherein the compositionhas a citrate concentration ([citrate]=[citric acid]+[dihydrogen citrateion]+[hydrogen citrate ion]+[citrate ion]) of at least about 10millimolar. Some embodiments described herein provide a pharmaceuticalcomposition comprising metoclopramide, or a pharmaceutically-acceptablesalt thereof, a citrate buffer, and optionally less than about 1% w/vbenzyl alcohol; wherein the composition is substantially free of color;and wherein the composition has a citrate concentration([citrate]=[citric acid]+[dihydrogen citrate ion]+[hydrogen citrateion]+[citrate ion]) of at least about 10 millimolar. Some embodimentsdescribed herein provide a pharmaceutical composition comprisingmetoclopramide, or a pharmaceutically-acceptable salt thereof, a citratebuffer, and optionally less than about 1% w/v benzyl alcohol; whereinthe composition is substantially clear; and wherein the composition hasa citrate concentration ([citrate]=[citric acid]+[dihydrogen citrateion]+[hydrogen citrate ion]+[citrate ion]) of at least about 10millimolar. In some embodiments, the concentration of benzyl alcohol isabout 0.01 to about 0.8% w/v, about 0.01 to about 0.5% w/v, about 0.01to about 0.25% w/v, about 0.01 to about 0.1% w/v, about 0.01 to about0.05% w/v. In some embodiments, the pharmaceutical composition remainsstable when stored in a package in which the composition is not incontact with oxygen. In some embodiments, the pharmaceutical compositiondoes not discolor when stored in a package in which the composition isnot in contact with oxygen. In some embodiments, the pharmaceuticalcomposition remains clear when stored in a package in which thecomposition is not in contact with oxygen. In some embodiments, thecomposition remains stable at a temperature of about 25° C. to about 40°C. for at least about 4 weeks, at least about 6 weeks, at least about 8weeks, at least about 10 weeks, at least about 12 weeks, at least about16 weeks, at least about 20 weeks or at least about 6 months. In someembodiments, the composition remains free of color at a temperature ofabout 25° C. to about 40° C. for at least about 4 weeks, at least about6 weeks, at least about 8 weeks, at least about 10 weeks, at least about12 weeks, at least about 16 weeks, at least about 20 weeks or at leastabout 6 months. In some embodiments, the composition remains clear at atemperature of about 25° C. to about 40° C. for at least about 4 weeks,at least about 6 weeks, at least about 8 weeks, at least about 10 weeks,at least about 12 weeks, at least about 16 weeks, at least about 20weeks or at least about 6 months. In some embodiments, the compositionhas a citrate concentration ([citrate]=[citric acid]+[dihydrogen citrateion]+[hydrogen citrate ion]+[citrate ion]) of at least about 10millimolar, at least about 15 millimolar, at least about 20 millimolar,about 10-100 millimolar, about 10-50 millimolar, about 10-25 millimolar,about 10-20 millimolar, about 10-15 millimolar, about 15-100 millimolar,about 15-50 millimolar, about 15-25 millimolar or about 15-20millimolar. In some embodiments, the pharmaceutical composition has astarting pH of at least about 4.5, at least about 4.6, at least about4.7, at least about 4.8, at least about 4.9, at least about 5.0, atleast about 5.1 or at least about 5.2, in a range of about 4.5-6.0, in arange of about 4.6-5.9, in a range of about 4.7-5.8, in a range of about4.8-5.7, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6,about 5.7, about 5.8, about 5.9 or about 6.0. In some embodiments, thecomposition is substantially free of any additional antioxidant. In someembodiments, the composition further comprises at least one member ofthe group consisting of a salt, EDTA, sorbitol, a sugar (including areduced sugar, such as sorbitol) or a flavoring agent. In someembodiments, the pharmaceutical composition has a concentration ofmetoclopramide, or a pharmaceutically-acceptable salt thereof, of fromabout 20.0% (w/v) to about 30.0% (w/v). In some embodiments, thepharmaceutical composition has a concentration of benzalkonium chloridefrom about 0.005% (w/v) to about 0.05% (w/v). In some embodiments, thepharmaceutical composition has an osmolality of from about 500 mOsm/kgto about 1400 mOsm/kg. In some embodiments, the osmolality is from about500 mOsm/kg to about 1000 mOsm/kg. In some embodiments, the osmolalityis from about 1000 mOsm/kg to about 1400 mOsm/kg.

Some embodiments provide a method of treating a patient, comprisingadministering to the patient an effective amount of a composition asdescribed herein. In some embodiments, the patient has a disorder thatis treatable with metoclopramide.

In some embodiments, the disorder that is treatable with metoclopramideis at least one member of the group consisting of gastroparesis, emesis,delayed emesis and nausea. In some embodiments, the disorder isgastroparesis. In some embodiments, the disorder is emesis or delayedemesis. In some embodiments, the disorder is nausea. In someembodiments, the composition is administered as one spray in one nostrilper day. In some embodiments, each spray contains about 10 mg to about20 mg of metoclopramide. In some embodiments, each spray contains about10 mg, about 15 mg or about 20 mg of metoclopramide. In someembodiments, the composition is administered as two sprays, one in eachnostril, per day. In some embodiments, each spray contains about 5 mg toabout 10 mg of metoclopramide. In some embodiments, each spray containsabout 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg or about 10mg of metoclopramide.

Some embodiments described herein provide for use of a metoclopramidesolution as described herein, for preparation of a medicament for thetreatment of a disorder that is treatable with metoclopramide. In someembodiments, the disorder that is treatable with metoclopramide is atleast one member of the group consisting of gastroparesis, emesis,delayed emesis and nausea. In some embodiments, the disorder isgastroparesis. In some embodiments, the disorder is emesis or delayedemesis. In some embodiments, the disorder is nausea. In someembodiments, the medicament is contained in a nasal administrationdevice, In some embodiments, the nasal administration device is adaptedor adaptable to deliver a pre-defined dose of metoclopramide per spray.In some embodiments, the predefined dose of metoclopramide is about 1 mgto about 25 mg per spray. In some embodiments, the predefined dose ofmetoclopramide is about 5 mg, about 10 mg, about 15 mg or about 20 mg ofmetoclopramide per spray. In some embodiments, the predefined dose ofmetoclopramide is about 5 mg, about 6 mg, about 7 mg, about 8 mg, about9 mg, about 10 mg, about 15 mg or about 20 mg of metoclopramide perspray.

Some embodiments described herein provide a manufacture comprising ametoclopramide pharmaceutical composition as described herein, and ameans for nasal administration of said composition to a patient. In someembodiments, the means for nasal administration comprises a reservoirthat contains the composition, a pump in fluid communication with thecomposition in the reservoir and a nozzle in fluid communication withthe pump, wherein activation of the pump withdraws a predeterminedamount of said composition from the reservoir and causes saidpredetermined amount of said composition to be expelled from saidnozzle. In some embodiments, the predetermined amount of composition isabout 10 μL to about 500 μL, about 50 μL to about 250 μL, about 50 μL,about 75 μL, about 100 μL, about 125 μL, about 150 μL, about 175 μL,about 200 μL, about 225 μL or about 250 μL per activation (“spray”). Inorder to combat the deleterious effects of light on metoclopramide, themanufacture may conveniently include a container, especially an opaquecontainer, i.e. a container that is at least partially or completelyimpervious to light. In some embodiments, a suitable opaque containerwill be brown or amber, especially brown or amber glass. In otherembodiments, the opaque container will be an opaque polymer container,such as is commonly used in the pharmaceutical arts.

Definitions

As used herein, the term “starting pH” is the pH of a solution at a timeprior to, or shortly after (<1 d), the solution being dispensed into avial or other unit dosage form suitable for nasal administration.

Citric acid (IUPAC Name 2-hydroxypropane-1,2,3-tricarboxylic acid) is anorganic acid having three carboxylic acid groups. In water, citric acidpartially dissociates to form dihydrogen citrate ion, hydrogen citrateion and citrate ion. The proportions of citric acid and its conjugateanions in a solution influence the pH of the solution, which is definedas −log₁₀ [H₃O].

As used herein the term “citrate” refers to the anion of citric acid inall its forms, i.e. fully protonated (citric acid), partiallydissociated (dihydrogen citrate ion: C₃H₇O(COO)₃ ⁻, hydrogen citrateion: C₃H₆O(COO)₃ ²⁻) and fully dissociated (citrate ion: C₃H₅O(COO)₃ ³⁻)forms. Where a particular ion of citric acid is intended, it will be sospecified, otherwise the term “citrate” by itself refers to the sum ofall protonated and ionic forms of citrate. Thus,[citrate]=[C₃H₈O(COO)₃]+[C₃H₇O(COO)₃]+[C₃H₆O(COO)₃ ²⁻]+[C₃H₅O(COO)₃³⁻]=[citric acid]+[dihydrogen citrate ion]+[hydrogen citrateion]+[citrate ion].

Benzalkonium chloride (also known as “alkyldimethylbenzylammoniumchloride”, “ADBAC” or simply “BAC”) is a mixture ofalkylbenzyldimethylammonium chlorides of various even-numbered alkylchain lengths. BAC, as used herein, has the formula:

wherein n is 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, etc; in some preferredembodiments, n is 8 to 18. Benzalkonium chloride USP NF is generallyused as a 50% w/v solution of BAC in water. Thus, in some embodiments,recited values of benzalkonium chloride (BAC) used herein refer to a 50%w/v solution of BAC in water. However, the values recited in the claimsrepresent the concentration (% w/v) of BAC in the final solution.

A nasal solution is substantially free of color when it is suitable forpharmaceutical administration, especially after storage, and inparticular after storage at accelerated conditions (e.g. 40° C./75% RH)for up to about 8 weeks, 6 months, or more. Where a particular degree ofclarity is intended, such will be recited with specificity. The UnitedStates Pharmacopoeia (USP) provides exemplary methodologies fordetermining the color of solutions, e.g. in 32 USP, NF 27, which isincorporated herein by reference. Color may be qualitatively judged bycomparing a nasal solution to one or more color reference standards.Suitable reference standards may be produced as set forth in the 32 USP<631>. An example of a suitable reference standard is reference standard“E” described in 32 USP <631>. Another example of a suitable referencestandard is a 50:50 dilution of reference standard “E” with water. Otherexamples of reference standards include reference standards A, B or Cdescribed in 32 USP <631>. In some instances, color may bequantitatively measured against a yellowish reference standard, such as0.0005 M iodine in water-at 450 nm. The absorbance of iodine under theseconditions has been measured to be 0.2440±0.0017 absorbance units. Thepercent optical density (% O.D.) is related to the absorbance of theiodine solution (Standard) as discussed herein below. Generally, a 200mg/mL solution of metoclopramide hydrochloride that is substantiallyfree of color after storage at 40° C./75% RH for 8 weeks has a % O.D. ofless than about 25%, e.g. less than about 23%, at 450 nm as compared toa 0.0005 M iodine in water solution. In some embodiments, a 200 mg/mLsolution of metoclopramide hydrochloride that is substantially free ofcolor after storage for 8 weeks under 40° C./75% RH conditions, has anabsorbance at 450 nm of less than 0.07 absorbance units, and especiallyless than about 0.06 absorbance units.

${\%\mspace{14mu}{OD}} = \frac{{Absorbance}\mspace{14mu}{of}\mspace{14mu}{Sample} \times 100\%}{{Absorbance}\mspace{14mu}{of}\mspace{14mu}{Standard}}$

wherein:

Absorbance of Standard is the absorbance at 450 nM of 0.0005 M iodine inwater; and

Absorbance of Sample is the absorbance at 450 nM of a metoclopramidehydrochloride sample as described herein.

In some embodiments, a “substantially free of color”, “substantiallyclear” or “stable” metoclopramide solution is one that is clear to paleyellow when compared to a standard prepared according to the followingstandard “E”, which is set forth at 32 USP <631>. The standard matchingsolution is prepared by combining 4.0 mL of cobaltous chloridecolorometric solution (USP CS), 12.0 mL of ferric chloride colorometricsolution (USP CS), and 3.0 mL of cupric sulfate solution (USP CS) into a50 mL volumetric flask and making the flask up to 50 mL with deionizedwater. Color determination is conducted by pipetting 5.0 mL of standardmatching solution into a 20 mL scintillation vial (about 15 mm height),pipetting 5.0 mL of sample solution into a separate 20 mL scintillationvial (about 15 mm height) and comparing the color of the two solutionsunder diffused day light against a vertical white background. In someembodiments, a sample whose color is clear, lighter than the standard orthe same color as the standard is considered “substantially free ofcolor”, “substantially clear” or “stable” as described herein.Objectivity may be ensured by having the color of a test solutionevaluated against the standard solution by more than one person.

In some embodiments, a “substantially free of color”, “substantiallyclear” or “stable” metoclopramide solution is one that is clear to paleyellow when compared to a standard prepared according to the followingstandard “C”, which is set forth at 32 USP <631>. The standard matchingsolution is prepared by combining 1.0 mL of cobaltous chloridecolorometric solution (USP CS), 4.0 mL of ferric chloride colorometricsolution (USP CS), and 1.0 mL of cupric sulfate solution (USP CS) into a50 mL volumetric flask and making the flask up to 50 mL with deionizedwater. Color determination is conducted by pipetting 5.0 mL of standardmatching solution into a 20 mL scintillation vial (about 15 mm height),pipetting 5.0 mL of sample solution into a separate 20 mL scintillationvial (about 15 mm height) and comparing the color of the two solutionsunder diffused day light against a vertical white background. In someembodiments, a sample whose color is clear, lighter than the standard orthe same color as the standard is considered “substantially free ofcolor”, “substantially clear” or “stable” as described herein.Objectivity may be ensured by having the color of a test solutionevaluated against the standard solution by more than one person.

In some embodiments herein, a stable metoclopramide solution is asolution in which the solution is pharmaceutically acceptable, e.g.wherein the active pharmaceutical ingredient meets the specifications ofa governmental pharmaceutical purity and efficacy regulatory body, suchas the United States Food and Drug Administration (FDA). In particularembodiments, a stable metoclopramide solution is a solution ofmetoclopramide which, after storage at 40° C./75% RH for 8 weeks, has apercent optical density (% O.D.) at 450 nm, relative to 0.0005 M iodinein water solution, of less than about 24% O.D. per 200 mg/mL ofmetoclopramide. Stability may be measured under accelerated conditions,such as high temperature and/or high humidity. In some embodiments, astable metoclopramide solution is a solution of metoclopramide which,when stored at 40° C./75% RH, demonstrates an average change in percentoptical density (% O.D.) at 450 nm, relative to 0.0005 M iodine in watersolution, of less than about 2% O.D. per week per 200 mg/mL ofmetoclopramide. In some embodiments, the change in % O.D. is measuredbetween weeks 1 and 8 of storage at 40° C./75% RH. In some embodiments,a stable metoclopramide solution is a solution of metoclopramide which,when stored at 40° C./75% RH, demonstrates an average change in percentoptical density (% O.D.) at 450 nm, relative to 0.0005 M iodine in watersolution, of less than about 1.8% O.D. per week per 200 mg/mL ofmetoclopramide. In some embodiments, the change in % O.D. is measuredbetween weeks 1 and 8 of storage at 40° C./75% RH. In some embodiments,the change in absorbance at 450 nm for a stable metoclopramide solutionof 200 mg/mL, measured between weeks 1 and 8 of storage at 40° C./75%RH, is less than about 0.004 absorbance units per week.

As used herein, “substantially free of any additional antioxidant” meansthat the solution contains no additional antioxidants other than thosethat are positively recited. In some embodiments, a solution may containcitrate, as defined herein, and be substantially free of any additionalantioxidant.

As used herein, “as an antioxidant”, especially in reference to citricacid, means that the ingredient is added in order to impart itsantioxidant value to the solution, and no conjugate salt of theingredient (e.g. citric acid) or other pH adjuster (e.g. sodiumhydroxide) is added to bring the solution to a particular pH. Thus, useof an ingredient “as an oxidant” is distinguished from use of the sameingredient as a buffer, where a particular pH or pH range is achieved byadding specific amounts of both acid and conjugate salt or base. Thisreflects the inventors' discovery that in some embodiments, addition ofan acid ingredient, such as citric acid, to a solution results instabilization of metoclopramide and protection of the solution againstcolor change, and that in some embodiments it is not necessary tocounter the acidity of said acid ingredient with a conjugate salt, or toform the conjugate salt in situ with addition of base, in order toachieve this stability and tendency not to change color.

As used herein, the indefinite articles “a” and “an” mean “at least one”unless otherwise stated. Likewise, the definite article “the”, unlessotherwise indicated, means “at least the” where the context permits ordemands it to be open-ended.

As used herein, a “nasal administration device” is a device capable ofadministering a dose of a composition comprising metoclopramide into thenose of a patient. In some embodiments, the nasal administration deviceis an atomizer, comprising a reservoir adapted to contain themetoclopramide solution and a pump adapted to draw a predeterminedamount of the metoclopramide solution from the reservoir dispense thepredetermined amount of metoclopramide solution through an atomizingnozzle and into at least one nostril of a patient. Suitable nasaladministration devices are commercially available

As used herein, the term “spray” indicates an atomized volume of liquidexpelled from a nozzle of a nasal administration device upon a singleactivation of the nasal administration device. In general, each spray isadministered into a single nostril of a patient.

As used herein, “metoclopramide” means metoclopramide(-amino-5-chloro-N-(2-(diethylamino)ethyl)-2-methoxybenzamide) or apharmaceutically acceptable salt thereof. Where reference is made to aparticular mass of metoclopramide, the recited mass is that of the freebase of metoclopramide, unless otherwise specified.

Buffers

In some embodiments, the nasal formulations of metoclopramide must havea pH of at least about 4.5, at least about 4.6, at least about 4.7, atleast about 4.8, at least about 4.9, at least about 5, at least about5.1 or at least about 5.2. In order to achieve and maintain anappropriate pH, it is considered necessary to use a buffer. Generally, abuffer comprises a combination of an acid (sometimes abbreviated HA) anda complementary base (A⁻). A buffer may be referred to by reciting theacid or the base that forms one half of the complementary acid-base(HA-A) pair. For example, acetic acid has the formula: CH₃C(O)OH, andforms a buffer with its complementary base, acetate ion, CH₃C(O)O⁻ inaqueous solution. The buffer so formulated may be referred to as anacetate buffer or as an acetic acid buffer. The person having skill inthe art will recognize that when the term buffer is used with either theacid or its complementary base, it refers to a mixture of the acid andthe free base in solution. Thus, a citrate buffer (or citric acidbuffer) refers to a mixture of citric acid and citrate ion. Since citricacid has three titratable groups, a citrate buffer (or citric acidbuffer) can refer to a mixture of citric acid, and one or more of thecomplementary bases resulting from removal of one, two or three of theprotons.

In some embodiments described herein, it is desirable to combine citricacid monohydrate and sodium citrate dihydrate in the nasal preparationin proportions suitable to provide a stable pH (+/−0.2 pH units) ofabout 4.5 and above, about 4.6 or above, about 4.7 or above, about 4.8or above, about 4.9 or above, about 5 or above, about 5.1 or above,about 5.2 or above, about 5.3 or above, about 4.5 to about 6.0, about4.6 to about 5.8, about 4.7 to about 5.6, about 4.5 to about 5.5, about4.6 to about 5.7, about 4.7 to about 5.8, about 5 to about 5.7, about5.1 to about 5.6. It is to be understood that the pH of the solution mayvary slightly upon storage, e.g. at accelerated or ambient conditions.Variance of 0.05 to ±0.4 pH units, ±0.1 to ±0.3 pH units or ±0.05 to±0.25 pH units may be noted upon storage.

In some embodiments provided herein, it is desirable to combine glacialacetic acid and sodium acetate trihydrate in the nasal preparation inproportions suitable to provide a stable pH (+/−0.2 pH units) of about4.5 and above, about 4.6 or above, about 4.7 or above, about 4.8 orabove, about 4.9 or above, about 5 or above, about 5.1 or above, about5.2 or above, about 5.3 or above, about 4.5 to about 6.0, about 4.6 toabout 5.8, about 4.7 to about 5.6, about 4.5 to about 5.5, about 4.6 toabout 5.7, about 4.7 to about 5.8, about 5 to about 5.7, about 5.1 toabout 5.6. Variance of ±0.05 to ±0.4 pH units, ±0.1 to ±0.3 pH units or±0.05 to ±0.25 pH units may be noted upon storage.

In some embodiments, a suitable buffer will have at least one pKa in arange of about 4.2 to about 5.5, about 4.3 to about 5.3. about 4.4 toabout 5.2, about 4.5 to about 5.1 or about 4.6 to about 5.0. In someembodiments, particularly desirable buffer will have a pKa in the rangeof about 4.7 to 4.8. In this regard, it is noted that acetic acid isreported to have a pKa of 4.75 and citric acid has three titratablegroups with pKa values of 3.13, 4.76 and 6.40, of which 4.76 is within arange considered desirable for preparing compositions according to thepresent invention. In some embodiments, other buffers may be used ifthey have the appropriate pKa and buffering capacity.

A buffer used in the formulations according to the present inventionshould possess sufficient buffering capacity to maintain the pH of thesolution within predetermined limits during storage. Buffering capacityof an acid/base buffer system may be influenced by various factors,among them being the total concentration of the buffer, which is thetotal concentration of the protonated (acid) form of the buffer and eachcomplementary base. In the case of a citrate buffer, the totalconcentration of the buffer should be at least about 30 mM, or at leastabout 45 mM or at least about 55 mM. In the case of acetate buffer, thetotal concentration of acetic acid and free acetate ion should begreater than about 70 mM, greater than about 80 mM or greater than about90 mM. In some embodiments, the buffering capacity of the selectedbuffer should be sufficient to maintain pH in the range of about ±0.1,0.2 or 0.3 pH units upon storage at 25° C. to about 45° C. for a periodof 2, 4, 6, 8, 10, 12, 16, 20, 24 or more weeks.

Some buffer systems that may be used in some embodiments ofmetoclopramide solutions as described herein include citricacid/phosphate, acetate, barbital, borate, Britton-Robinson, cacodylate,citrate, collidine, formate, maleate, McIlvaine, phosphate,Prideaux-Ward, succinate, citrate-phosphate-borate (Teorell-Stanhagen),veronal acetate, MES (2-(N-morpholino)ethanesulfonic acid), BIS-TRIS(bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA(N-(2-acetamido)-2-iminodiacetic acid), ACES(N-(carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES(piperazine-N,N′-bis(2-ethanesulfonic acid)), MOPSO(3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE(1,3-bis(tris(hydroxymethyl)methylamino)propane), BES(N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS(3-(N-morpholino)propanesulfonic acid), TES(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), DIPSO(3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS(4-(N-morpholino)butanesulfonic acid), TAPSO(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxy-propanesulfonic acid),tris(hydroxymethylaminomethane, HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid), POPSO(piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)), TEA(triethanolamine), EPPS(N-(2-hydroxyethyl)piperazine-N′-(3-propane-sulfonic acid), TRICINE(N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE(N,N-bis(2-hydroxyethyl)glycine), HEPBS(N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid)), TAPS(N-tris(hydroxy-methyl)methyl-3-aminopropanesulfonic acid), or AMPD(2-amino-2-methyl-1,3-propanediol) buffer. In some embodiments, otherpharmaceutically acceptable buffers may be used.

Antioxidants

In some embodiments, nasal compositions of metoclopramide may includeone or more antioxidants suitable for administration to the nose ornasal cavity. In some embodiments, such antioxidants can includebutylated hydroxyanisole, citric acid, citric acid monohydrate, sodiumcitrate dihydrate, or combinations of two or more thereof. In someparticular embodiments, the antioxidant can include citric acid and/orsodium citrate.

Particular Excipients

In some embodiments, nasal compositions of metoclopramide may includeone or more particular excipients suitable for administration to thenose or nasal cavity. In some embodiments, such excipients can includecitric acid, sodium citrate, benzalkonium chloride, sorbitol, EDTA, orcombinations of two or more thereof. In some particular embodiments, theexcipients can include citric acid and/or sodium citrate. In someembodiments, the excipients can include benzalkonium chloride or acombination of benzalkonium chloride and citric acid and/or sodiumcitrate. In some embodiments, the excipients can include a combinationof benzalkonium chloride and sorbitol, optionally with the addition ofone or both of citric acid and sodium citrate.

Formulation of Nasal Compositions of Metoclopramide (Use for Productionof a Medicament)

Nasal compositions of metoclopramide may be manufactured foradministration as a medicament for administration to a patient for oneof the indications described herein. Briefly, metoclopramide, buffer,benzalkonium chloride and optionally other ingredients (such as sodiumchloride or other osmolarity-regulating agent, sorbitol or othersweetener, flavoring agent, etc.) may be made up to some volume lessthan the target final volume of the solution. The ingredients may thenbe mixed until all the ingredients are dissolved. The pH then may beadjusted, if necessary, by addition of a suitable acid or base, such asHCl, NaOH, or the complementary acid or base of the buffer. Once thedesired pH has been obtained, the solution may then be brought up tofull volume with water. The resulting solution may then be packaged in asuitable container for shipping and distribution. In some embodiments,the suitable container includes a nasal pump as described in more detailbelow. In other embodiments, the suitable container may be a vial, suchas an amber glass vial, which may be a glass ampule, a glass bottletopped with an inert rubber septum and crimp cap top, or other suitablepharmaceutical vial.

Manufacture

Some embodiments described herein provide, as a manufacture, acombination of a stable, clear and/or colorless solution ofmetoclopramide and a means for intranasal administration of themetoclopramide solution. In some embodiments, the manufacture comprisesone of the metoclopramide solutions described herein and an intranasaldelivery device comprising a reservoir, in which the metoclopramidesolution is contained, a pump in fluid communication with the reservoirand a nozzle in fluid communication with the pump. In use, the pump isactuated, drawing an amount of the metoclopramide solution from thereservoir and expelling the solution out of the nozzle as an aerosolizedspray. Suitable nasal administration devices are commercially available.Among the suppliers of nasal administration devices that may be combinedwith a stable, substantially clear and/or substantially colorlessmetoclopramide solution according to the present invention, there may bementioned Valois of America, Congers, New York, and Pfeiffer of America,Princeton, N.J. In some embodiments, the intranasal delivery device ispartially or completely opaque, in order to protect the contents of thedevice from exposure to ambient light.

Stability of Nasal Compositions of Metoclopramide

Compositions described herein comprise metoclopramide, or apharmaceutically acceptable salt thereof, in a stable composition. Insome embodiments described herein, stable metoclopramide solutions aresolutions containing metoclopramide characterized by color stability orclarity of the solution. In some embodiments, color stability refers tothe tendency of a formulated solution to maintain the same color, orabsence of color, upon storage for a predetermined period of time as ithad when originally formulated. In some embodiments, stability refers tothe tendency of a formulated solution to maintain the same clarity uponstorage for a predetermined period of time as it had when originallyformulated. In some embodiments, stability refers to the tendency of aformulated solution to resist degradation of one or more ingredients,and in particular metoclopramide, during storage. In some embodiments,such compositions are stable for a period of at least about 1 month, atleast about 2 months, at least about 3 months, at least about 4 months,at least about 5 months, at least about 6 months, at least about 9months, at least about 12 months, at least about 15 months, at leastabout 18 months, at least about 21 months or at least about 24 months attemperatures in the range of about 5° C. to about 25° C. In someembodiments, long-term storage at 5°-25° C. may be simulated underaccelerated conditions, e.g. at a temperature in the range of about 35°C. to about 60° C., particularly in a range of about 35° C. to about 45°C., e.g. about 40° C. Thus, in some embodiments, the nasal compositionsof metoclopramide provided herein are stable upon storage underaccelerated conditions, e.g. at about 25° C. to about 60°, especially atabout 30° C. to about 50° C., about 35° C. to about 45° C. or about 40°C. for at least about 1 week, at least about 2 weeks, at least about 3weeks, at least about 4 weeks, at least about 5 weeks, at least about 6weeks, at least about 9 weeks, at least about 12 weeks, at least about15 weeks, at least about 18 weeks, at least about 21 weeks or at leastabout 24 weeks.

Stability may be determined by methods known in the art, such as thosedictated by the United States Pharmacopoeia (USP). In particular, USP26, pages 500-502, and 2138-2140 (incorporated herein by reference)provide general procedures for preparing standard colored solutions forcolor determination and for determining the color or achromicity of asolution. Thus, the person skilled in the art will know how to preparestandard solutions and compare the color of a composition of theinvention against standard solutions. 32 USP <631>, pages 238-239(incorporated herein by reference) provide standardized methods formeasuring the stability of metoclopramide in injectable and oralsolutions of metoclopramide. The person skilled in the art would thusknow how to test the stability of metoclopramide compositions. Colorstandards can also include standards A, B, C, D and/or E described in 32USP <631>. In some embodiments, another color standard that may beuseful for determining the stability of nasal metoclopramide solutionsis the a 50:50 dilution of standard C with distilled water, wherein C isas described in 32 USP <631>. The 50:50 dilution of C with distilledwater is also referred to herein at 0.5 C, and can be prepared bycombining 1 mL Cobaltous Chloride CS, 6 mL Ferric Chloride CS, 1 mLCupric Sulfate CS, and q.s. to 50 mL with distilled water to producestandard C and then diluting C to 0.5 C by combining 1 part C with 1part distilled water. A solution that is lighter than 0.5 C isconsidered to be substantially clear as the term is used herein. TheCobaltous Chloride CS, Ferric Chloride CS and Cupric Sulfate CS arecolorometric solutions are commercially available; they may also beprepared according to 32 USP under Colorimetric Solutions (CS) in thesection Reagents, Indicators, and Solutions, which is incorporated byreference herein in its entirety. In some other preferred embodiments,the color reference standard is “E” from 32 USP <631>. The standardmatching solution “E” is prepared by combining 4.0 mL of cobaltouschloride colorometric solution (USP CS), 12.0 mL of ferric chloridecolorometric solution (USP CS), and 3.0 mL of cupric sulfate solution(USP CS) into a 50 mL volumetric flask and making the flask up to 50 mLwith deionized water. Color determination is conducted by pipetting 5.0mL of standard matching solution into a 20 mL scintillation vial (about15 mm height), pipetting 5.0 mL of sample solution into a separate 20 mLscintillation vial (about 15 mm height) and comparing the color of thetwo solutions under diffused day light against a vertical whitebackground. In some embodiments, a sample whose color is clear, lighterthan the standard or the same color as the standard is considered“substantially free of color”, “substantially clear” or “stable” asdescribed herein. Objectivity may be ensured by having the color of atest solution evaluated against the standard solution by more than oneperson.

In some embodiments, the metoclopramide compositions described hereinare colorless when formulated and remain colorless for a period of atleast about 2 weeks, about 1 month, at least about 2 months, at leastabout 3 months, at least about 4 months, at least about 5 months, atleast about 6 months, at least about 9 months, at least about 12 months,at least about 15 months, at least about 18 months, at least about 21months or at least about 24 months at temperatures in the range of about5° C. to about 25° C. In some embodiments, long-term storage at 5°-25°C. may be simulated under accelerated conditions, e.g. at a temperaturein the range of about 35° C. to about 60° C., particularly in a range ofabout 35° C. to about 45° C., e.g. about 40° C. Thus, in someembodiments, the nasal compositions of metoclopramide provided hereinare colorless when formulated and remain colorless upon storage underaccelerated conditions, e.g. at about 25° C. to about 60°, especially atabout 30° C. to about 50° C., about 35° C. to about 45° C. or about 40°C. for at least about 1 week, at least about 2 weeks, at least about 3weeks, at least about 4 weeks, at least about 5 weeks, at least about 6weeks, at least about 9 weeks, at least about 12 weeks, at least about15 weeks, at least about 18 weeks, at least about 21 weeks or at leastabout 24 weeks.

Methods of Treatment with Nasally Administered Metoclopramide

Pharmaceutical formulations described herein may be employed in methodsfor the treatment of one or more disease states treatable withmetoclopramide. In some embodiments, the pharmaceutical compositions canbe used to treat a patient for gastroparesis, emesis, delayed emesis ornausea, or any combination of two or more of these indications.

In some embodiments provided herein, gastroparesis is treated byintranasal instillation of a pharmaceutically active amount of ametoclopramide solution described herein. Metoclopramide nasal dosageform at a therapeutic dosage level of between about 20 mg/day to about160 mg/day for about 1 to about 8 weeks, about 5 weeks to about 8 weeks,or about 1, 2, 3, 4, 5, 6, 7, 8 or more weeks.

In some embodiments, a method for treating gastroparesis comprisesintranasally administering a nasal metoclopramide composition asdescribed herein at a metoclopramide dosage of about 40 mg/day to about160 mg/day in 3 to 4 smaller dosages at equally spaced intervals within24 hours for about 1 to about 8 weeks, about 2 to 6 weeks or about 1, 2,3, 4, 5, 6, 7, 8 or more weeks. Daily dosing may be varied according tothe particular characteristics of the various patients. A clinicalpractitioner or pharmacist will be able to modify the administereddosage and dosing regimen in order to treat the particular patient. Insome embodiments, from 1 to about 8, from 1 to 4 or 1, 2, 3, 4, 5, 6, 7,8 or more doses may be administered in a day, depending upon the needsand tolerance of the patient. In some embodiments, a therapeutic dosagelevel of metoclopramide will be from about 20 mg/day to about 160mg/day, about 30 mg/day, about 35 mg/day, about 40 mg/day, about 45mg/day, about 55 mg/day, about 60 mg/day, about 65 mg/day, about 70mg/day, about 75 mg/day, about 80 mg/day, about 85 mg/day, about 90mg/day, about 95 mg/day, about 100 mg/day, about 105 mg/day, about 110mg/day, about 115 mg/day, about 120 mg/day, about 125 mg/day, about 130mg/day, about 135 mg/day, about 140 mg/day, about 145 mg/day, about 150mg/day, about 155 mg/day, about 160 mg/day. These daily dosages may bebroken into smaller doses, which may be spread over different parts of aday. Smaller doses may be about 5 to about 30 mg, e.g. about 5 mg, about10 mg, about 15 mg, about 20 mg, about 25 mg or about 30 mg.Administration of about 3-4 smaller dosages at equally spaced intervalswithin a 24-hour period or about 1-8 weeks is contemplated.Administration may be prescribed before meals, assuming 2 to 4 meals perday, and before bedtime.

In some embodiments, the method comprises treatment of gastroparesis ofvarying etiology, including gastroparesis arising out, associated withor caused by diabetes (including type 1 and type 2), postviralsyndromes, anorexia nervosa, surgery on the stomach or vagus nerve,medications, such as anticholinergic and narcotic medications, whichtend to suppress intestinal and gastroesophageal contractions,gastroesophageal reflux disease, smooth muscle disorders (e.g.amyloidosis and scleroderma), nervous system diseases (includingabdominal migraine and Parkinson's disease), and/or metabolic disorders(including hypothyroidism).

In some embodiments, the gastroparesis is of diabetic origin, includingtype 1 and type 2 diabetes and treatment comprises intranasallyadministering a nasal composition of metoclopramide as described hereinin a nasal spray dosage form and at a therapeutic dosage level ofbetween about 40 mg/day to about 160 mg/day in 3 to 4 smaller dosages atequally spaced intervals within 24 hours for about 1 to about 8 weeks,for about 2 weeks to about 8 weeks or for 1, 2, 3, 4, 5, 6, 7, 8 or moreweeks.

In some embodiments, treatment comprises intranasally administering anasal composition of metoclopramide as described here at a therapeuticdosage level of between about 40 mg/day to about 80 mg/day in 3 to 4smaller dosages at equally spaced intervals within 24 hours for about 1to about 8 weeks, for about 2 weeks to about 8 weeks or for 1, 2, 3, 4,5, 6, 7, 8 or more weeks.

In some embodiments provided herein, emesis, delayed emesis or nausea istreated by intranasal instillation of a pharmaceutically active amountof a metoclopramide solution described herein. Metoclopramide nasaldosage form at a therapeutic dosage level of between about 20 mg/day toabout 160 mg/day for about 1 to about 8 weeks, about 5 weeks to about 8weeks, or about 1, 2, 3, 4, 5, 6, 7, 8 or more weeks.

In some embodiments, a method for treating, emesis, delayed emesis ornausea comprises intranasally administering a nasal metoclopramidecomposition as described herein at a metoclopramide dosage of about 40mg/day to about 160 mg/day in 3 to 4 smaller dosages at equally spacedintervals within 24 hours for about 1 to about 8 weeks, about 2 to 6weeks or about 1, 2, 3, 4, 5, 6, 7, 8 or more weeks. Daily dosing may bevaried according to the particular characteristics of the variouspatients. A clinical practitioner or pharmacist will be able to modifythe administered dosage and dosing regimen in order to treat theparticular patient. In some embodiments, from 1 to about 8, from 1 to 4or 1, 2, 3, 4, 5, 6, 7, 8 or more doses may be administered in a day,depending upon the needs and tolerance of the patient. In someembodiments, a therapeutic dosage level of metoclopramide will be fromabout 20 mg/day to about 160 mg/day, about 30 mg/day, about 35 mg/day,about 40 mg/day, about 45 mg/day, about 55 mg/day, about 60 mg/day,about 65 mg/day, about 70 mg/day, about 75 mg/day, about 80 mg/day,about 85 mg/day, about 90 mg/day, about 95 mg/day, about 100 mg/day,about 105 mg/day, about 110 mg/day, about 115 mg/day, about 120 mg/day,about 125 mg/day, about 130 mg/day, about 135 mg/day, about 140 mg/day,about 145 mg/day, about 150 mg/day, about 155 mg/day, about 160 mg/day.These daily dosages may be broken into smaller doses, which may bespread over different parts of a day. Smaller doses may be about 5 toabout 30 mg, e.g. about 5 mg, about 10 mg, about 15 mg, about 20 mg,about 25 mg or about 30 mg. Administration of about 3-4 smaller dosagesat equally spaced intervals within a 24-hour period or about 1-8 weeksis contemplated. Administration may be prescribed before meals, assuming2 to 4 meals per day, and before bedtime.

In some embodiments, a pharmaceutical composition administered for thetreatment of one or more clinical indications as described hereinconsists of: metoclopramide (e.g. as metoclopramide HCl), citric acid(e.g. as the monohydrate), sodium citrate (e.g. as the dihydrate),benzalkonium chloride (e.g. as a 50% solution, N.F.), sorbitol (e.g. asa solution, such as a 70% solution USP), edetate disodium, sodiumchloride and purified water. In some embodiments, a pharmaceuticalcomposition administered for the treatment of one or more clinicalindications described herein consists of: metoclopramide (e.g. asmetoclopramide HCl), citric acid (e.g. as the monohydrate), sodiumcitrate (e.g. as the dihydrate), benzalkonium chloride (e.g. as a 50%solution, N.F.), edetate disodium, sodium chloride and purified water.In some embodiments, a pharmaceutical composition administered for thetreatment of one or more clinical indications described herein consistsof: metoclopramide (e.g. as metoclopramide HCl), citric acid (e.g. asthe monohydrate), sodium citrate (e.g. as the dihydrate), benzalkoniumchloride (e.g. as a 50% solution, N.F.), sodium chloride and purifiedwater.

In some embodiments, a pharmaceutical composition administered for thetreatment of one or more clinical indications as described hereinconsists of: metoclopramide (e.g. as metoclopramide HCl, 15-30% w/v,20-25% w/v or 22-24% w/v), citric acid (e.g. as the monohydrate,0.2-0.5% w/v, 0.25-0.4% w/v or 0.3-0.35% w/v), sodium citrate (e.g. asthe dihydrate, 1.0-1.8% w/v, 1.2-1.6% w/v or about 1.3-1.5% w/v),benzalkonium chloride (e.g. as a 50% solution, N.F., about 0.01-0.05%w/v, about 0.02-0.04% w/v or about 0.02-0.03% w/v), sorbitol (e.g. as asolution, such as a 70% solution USP, about 1-5% w/v, about 2-4% w/v orabout 2.5-3.5% w/v), edetate disodium, sodium chloride and purifiedwater. In some embodiments, a pharmaceutical composition administeredfor the treatment of one or more clinical indications described hereinconsists of: metoclopramide (e.g. as metoclopramide HCl, 15-30% w/v,20-25% w/v or 22-24% w/v), citric acid (e.g. as the monohydrate,0.2-0.5% w/v, 0.25-0.4% w/v or 0.3-0.35% w/v), sodium citrate (e.g. asthe dihydrate, 1.0-1.8% w/v, 1.2-1.6% w/v or about 1.3-1.5% w/v),benzalkonium chloride (e.g. as a 50% solution, N.F., about 0.01-0.05%w/v, about 0.02-0.04% w/v or about 0.02-0.03% w/v), edetate disodium,sodium chloride and purified water. In some embodiments, apharmaceutical composition administered for the treatment of one or moreclinical indications described herein consists of: metoclopramide (e.g.as metoclopramide HCl, 15-30% w/v, 20-25% w/v or 22-24% w/v), citricacid (e.g. as the monohydrate, 0.2-0.5% w/v, 0.25-0.4% w/v or 0.3-0.35%w/v), sodium citrate (e.g. as the dihydrate, 1.0-1.8% w/v, 1.2-1.6% w/vor about 1.3-1.5% w/v), benzalkonium chloride (e.g. as a 50% solution,N.F., about 0.01-0.05% w/v, about 0.02-0.04% w/v or about 0.02-0.03%w/v), sodium chloride and purified water. The amount of edetatedisodium, if present, may be between about 0.01 and 0.2% w/v, e.g. about0.05-0.15% w/v or about 0.1% w/v. The amount of sodium chloride may beadjusted to attain a desirable osmolality for the solution. Suitableconcentrations of sodium chloride include about 0.1-2.0% w/v, 0.2-1.5%w/v and 0.5-1.0% w/v. A suitable acid or base may be added to attain thedesired pH. Such acids and bases include HCl and NaOH. A suitable pH maybe in the range of about pH 4.5-6.0, e.g. about 4.7-5.7 or about4.8-5.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about5.2, about 5.3, about 5.4, about 5.5, about 5.6 or about 5.7.

In some embodiments, a pharmaceutical composition administered for thetreatment of one or more clinical indications as described hereinconsists of: metoclopramide (e.g. as metoclopramide HCl), acetic acid(e.g. as glacial acetic acid), sodium acetate (e.g. as the trihydrate),benzalkonium chloride (e.g. as a 50% solution, N.F.), sorbitol (e.g. asa solution, such as a 70% solution USP), edetate disodium, sodiumchloride and purified water. In some embodiments, a pharmaceuticalcomposition administered for the treatment of one or more clinicalindications described herein consists of: metoclopramide (e.g. asmetoclopramide HCl), acetic acid (e.g. as glacial acetic acid), sodiumacetate (e.g. as the trihydrate), benzalkonium chloride (e.g. as a 50%solution, N.F.), edetate disodium, sodium chloride and purified water.In some embodiments, a pharmaceutical composition administered for thetreatment of one or more clinical indications described herein consistsof: metoclopramide (e.g. as metoclopramide HCl), acetic acid (e.g. asglacial acetic acid), sodium acetate (e.g. as the trihydrate),benzalkonium chloride (e.g. as a 50% solution, N.F.), sodium chlorideand purified water.

In some embodiments, a pharmaceutical composition administered for thetreatment of one or more clinical indications as described hereinconsists of: metoclopramide (e.g. as metoclopramide HCl, 15-30% w/v,20-25% w/v or 22-24% w/v), acetic acid (e.g. as glacial acetic0.02-0.10% w/v, 0.03-0.08% w/v or 0.04-0.07% w/v), sodium acetate (e.g.as the trihydrate, 0.4-1.0% w/v, 0.5-0.9% w/v or 0.4-0.8% w/v),benzalkonium chloride (e.g. as a 50% solution, N.F., about 0.01-0.05%w/v, about 0.02-0.04% w/v or about 0.02-0.03% w/v), sorbitol (e.g. as asolution, such as a 70% solution USP, about 2-10% w/v, about 4-8% w/v orabout 5-7% w/v), edetate disodium, sodium chloride and purified water.In some embodiments, a pharmaceutical composition administered for thetreatment of one or more clinical indications described herein consistsof: metoclopramide (e.g. as metoclopramide HCl, 15-30% w/v, 20-25% w/vor 22-24% w/v), acetic acid (e.g. as glacial acetic 0.02-0.10% w/v,0.03-0.08% w/v or 0.04-0.07% w/v), sodium acetate (e.g. as thetrihydrate, 0.4-1.0% w/v, 0.5-0.9% w/v or 0.4-0.8% w/v), benzalkoniumchloride (e.g. as a 50% solution, N.F., about 0.01-0.05% w/v, about0.02-0.04% w/v or about 0.02-0.03% w/v), edetate disodium, sodiumchloride and purified water. In some embodiments, a pharmaceuticalcomposition administered for the treatment of one or more clinicalindications described herein consists of: metoclopramide (e.g. asmetoclopramide HCl, 15-30% w/v, 20-25% w/v or 22-24% w/v), acetic acid(e.g. as glacial acetic 0.02-0.10% w/v, 0.03-0.08% w/v or 0.04-0.07%w/v), sodium acetate (e.g. as the trihydrate, 0.4-1.0% w/v, 0.5-0.9% w/vor 0.4-0.8% w/v), benzalkonium chloride (e.g. as a 50% solution, N.F.,about 0.01-0.05% w/v, about 0.02-0.04% w/v or about 0.02-0.03% w/v),sodium chloride and purified water. The amount of edetate disodium, ifpresent, may be between about 0.01 and 0.2% w/v, e.g. about 0.05-0.15%w/v or about 0.1% w/v. The amount of sodium chloride may be adjusted toattain a desirable osmolality for the solution. Suitable concentrationsof sodium chloride include about 0.1-2.0% w/v, 0.2-1.5% w/v and 0.5-1.0%w/v. A suitable acid or base may be added to attain the desired pH. Suchacids and bases include HCl and NaOH. A suitable pH may be in the rangeof about pH 4.5-6.0, e.g. about 4.7-5.7 or about 4.8-5.6, about 4.7,about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about5.4, about 5.5, about 5.6 or about 5.7.

The nasal metoclopramide compositions described herein may beadministered a patient as 1 spray in a single nostril, four times a day(1 spray QID for about 1, 2, 3, 4, 5, 6, 7, or 8 weeks), or 1 spray pernostril in both nostrils four times a day (2 sprays QID for about 1, 2,3, 4, 5, 6, 7, or 8 weeks). Those skilled in the art (e.g. cliniciansand pharmacists) will recognize that a systemic, therapeuticallyeffective amount of metoclopramide for treating gastroparesis, emesis,delayed emesis, nausea or a combination of two or more thereof, willvary with the age, size, weight and general physical condition of thepatient, as well as the severity of the disease. Frequency ofadministration will likewise vary with the formulation of nasalmetoclopramide (i.e., the concentration of metoclopramide, whether it isin the form of sustained release, etc.) and can be adjusted so that anysuitable number of doses per day may be used.

The methods of treatment provided herein can also includeco-administration of one or more additional therapeutic agents alongwith the metoclopramide nasal formulations described herein. Theadditional therapeutic agents administered concurrently withmetoclopramide or at separate time intervals. In some embodiments, oneor more other drugs may be incorporated into the metoclopramide nasalformulation. Additional therapeutic agents may include pain relievers,insulin and other drugs useful in the management of diabetes, steroids,especially steroids that prevent nasal irritation, and antidepressants.

Various techniques may be used to assess the severity of thegastroparesis and gastric emptying, and these will be well-known tothose of skill in the art. Such techniques include questioning thepatient regarding symptoms of gastroparesis. Techniques like radioscintigraphy, ultrasonography, and x-rays employing radiopaque markerssuch as barium, may be employed.

As the weight of the patient may affect the dosage to be administered,the person skilled in the art will know to vary or titrate the dose inorder to obtain an optimal effect in relation to the dose tolerated bythe patient. For example, a dose of between about 0.1 mg/kg to about 2.5mg/kg may be administered to a patient having gastroparesis. Exemplarydosages can be about 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1.0 mg/kg, 1.1 mg/kg,1.2 mg/kg, 1.3 mg/kg, 1.4 mg/kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8mg/kg, 1.9 mg/kg, 2.0 mg/kg, 2.1 mg/kg, 2.2 mg/kg, 2.3 mg/kg, 2.4 mg/kg,2.5 mg/kg. In some embodiments, a nasal dosage is between about 0.06 toabout 1.2 mg/kg of body weight. In some embodiments, the nasal dosagesare about 0.06 mg/kg, 0.08 mg/kg, 1.0 mg/kg, 1.2 mg/kg and 1.4 mg/kg.

The aforementioned dosages for the treatment and control ofgastroparesis may be administered before meals and/or before bed time.

EXAMPLES Comparative Example 1: Discoloration of MetoclopramideSolutions

In order to evaluate the stability of metoclopramide solutions, variouscompositions comprising metoclopramide are prepared according to thefollowing Table CX1-1. These compositions are set up on stability underaccelerated conditions (40° C./75% RH) for 1, 2, 4, or 8 weeks.

TABLE CX1-1 Sample CX 1, CX 2 CX 3 CX 4 CX 5 CX 6 CX 7 CX 8 CX 9 CX 10Metoclopramide 400 mg/mL & 200 mg/mL 200 mg/mL 200 mg/mL 100 mg/mL 100mg/mL 100 mg/mL 100 mg/mL 200 mg/mL 200 mg/mL Acetic Acid 3.20 — 3.203.20 3.20 3.20 3.20 3.20 3.20 (mg/mL) Acetic Acid 0.0533 — 0.0533 0.05330.0533 0.0533 0.0533 0.0533 0.0533 (mmol/mL) Sodium 0.77 — 0.77 0.770.77 0.77 0.77 0.77 0.77 Acetate (mg/mL) Sodium 0.0094 — 0.0094 0.00940.0094 0.0094 0.0094 0.0094 0.0094 Acetate (mmol/mL) Citric Acid — 0.16— — — — — — — (mg/mL) Citric Acid — 0.0020 — — — — — — — (mmol/mL)Sodium — 0.50 — — — — — — — Citrate (mg/mL) Sodium — 0.0026 — — — — — —— Citrate (mmol/mL) NaCl 8.00 — 8.00 8.00 — — — — — Sorbitol 64.3 — 64.264.2 — — — — — EDTA — — — 1.0 — — — — — BAC — 0.40 — — — — — — —Benzyl-OH 15.0 — 15.0 15.0 — — — — — pH Calc. 4.00 4.89 4.00 4.00 4.004.00 4.00 4.00 4.00 Total 0.063 0.005 0.063 0.063 0.063 0.063 0.0630.063 0.063 Buffer (mmol/mL) ----- ---- ---- ---- ---- ---- ---- -------- ---- pH Calc. 4.00 4.89 4.00 4.00 4.00 4.00 4.00 4.00 4.00 Total0.063 0.005 0.063 0.063 0.063 0.063 0.063 0.063 0.063 Buffer (mmol/mL)

Each of the solutions become substantially colored upon storage underthe conditions outlined above, the discoloration tending from a verylight yellow to a darker yellow-brown.

Example 1: Formulation of Nasally Administrable MetoclopramideCompositions

Several metoclopramide solutions were prepared in order to evaluate thestability, clarity and/or tendency to become colored on storage ofvarious formulations. The composition of these solutions are set forthin the following Table 1-1, where the compositions are numbered 1-10.These compositions were filled into two different samples of pumps(Valois) attached to amber glass vials and were stored at 40° C./75% RHand were observed at the end of 2, 4 and 8 weeks. The results of thesestudies are shown in Table 1-1.

TABLE 1-1 Composition of formulations 1-10 Formulation Number Ingredient1 2 3 4 5 6 7 8 9 10 Metoclopramide 23.64 23.64 23.64 23.64 23.64 23.6423.64 23.64 23.64 23.64 HCL USP mg/mL Acetic Acid 0.57 — — — 0.57 0.570.57 0.57 0.57 — (mg/mL) Acetic Acid 0.0095 — — — 0.0095 0.0095 0.00950.0095 0.0095 — (mmol/mL) Sodium 7.28 — — — 7.28 7.28 7.28 7.28 7.28 —Acetate (mg/mL) Sodium 0.0535 — — — 0.0535 0.0535 0.0535 0.0535 0.0535 —Acetate (mmol/mL) Citric Acid — 1.00 1.00 1.00 — — — — — 1.00 (mg/mL)Citric Acid — 0.0048 0.0048 0.0048 — — — — — 0.0048 (mmol/mL) Sodium —4.40 4.40 4.40 — — — — — 4.40 Citrate (mg/mL) Sodium — 0.0150 0.01500.0150 — — — — — 0.0150 Citrate (mmol/mL) NaCl 8.00 8.00 — — — — — — — —Sorbitol 3.0 3.0 — — — 3.0 3.0 — — EDTA 1.0 1.0 1.0 — — 1.0 1.0 1.0 1.01.0 BAC 0.25 0.25 0.25 0.25 0.25 — — 0.25 0.25 — Menthol 0.80 — — — 0.80— — — — — Benzyl-OH — — — — — 7.5 7.5 — — 7.5 Methocel — — — — — — — — —— mOsm 1233 1286 693 693 820 1067 787 1042 759 755 pH Initial 5.36 5.345.41 5.40 5.37 5.62 5.64 5.58 5.62 5.42 pH Week 2 5.20 5.16 5.24 5.145.22 5.40 5.58 5.38 5.44 5.12 ΔpH −0.16 −0.18 −0.17 −0.26 −0.15 −0.22−0.06 −0.20 −0.18 −0.30 % Δph −2.99 −3.37 −3.14 −4.81 −2.79 −3.91 −1.06−3.58 −3.20 −5.54 Total Buffer 0.063 0.020 0.020 0.020 0.063 0.063 0.0630.063 0.063 0.020 (mmol/mL)

Tables 1-2A and 1-2B set forth results of stability studies performed inPfeiffer pumps at 40° C./75% RH at 4 and 8 week time points. Table 1-2Acontains the data for Sample 1 (first set of pumps), and Table 1-2Bcontains the data for Sample 2 (second set of pumps) from this study.

TABLE 1-2A (Sample 1) Composition Color: Week 4 Color: Week 8 1 ND ND 2ND ND 3 ND ND 4 ND ND 5 ND VLBS 6 VLBS LBS 7 VLBS LBS 8 ND ND 9 ND ND 10VLBS VLBS

TABLE 1-2B (Sample 2) Formulation Color: Week 4 Color: Week 8 1 ND ND 2ND ND 3 ND ND 4 ND ND 5 ND ND 6 VLBS VLBS 7 VLBS VLBS 8 ND ND 9 ND ND 10VLBS VLBSKey for Tables 1-2A, 1-2B:

-   -   ND=Substantially Free of Color Brown    -   BS=Solution    -   LBS=Light Brown Solution    -   VLBS=Very Light Brown Solution

Tables 1-3A and 1-3B show the results of a stability study carried outin Valois pumps at 40° C./75% RH, with observations taken at 2, 4 and 8week time points. Table 1-3A contains the data for Sample 1 and Table1-3B contains the data for Sample 2 from this study.

TABLE 1-3A Composition Color: Week 2 Color: Week 4 Color: Week 8 1 ND NDND 2 ND ND ND 3 ND ND ND 4 ND ND ND 5 ND ND ND 6 VLBS VLBS VLBS 7 VLBSVLBS VLBS 8 ND ND ND 9 ND ND ND 10 VLBS VLBS VLBS

TABLE 1-3B Formulation Week 2 Week 4 Week 8 1 ND ND ND 2 ND ND ND 3 NDND ND 4 ND ND ND 5 ND ND ND 6 VLBS VLBS VLBS 7 VLBS VLBS VLBS 8 ND ND ND9 ND ND ND 10 VLBS VLBS VLBS

Key for Tables 1-3A, 1-3B

-   -   ND=Substantially Free of Color Brown    -   BS=Solution    -   LBS=Light Brown Solution    -   VLBS=Very Light Brown Solution

As can be seen in Tables 1-2A, 1-2B, 1-3A and 1-3B, compositions 1-5 and8-9 remained substantially free of color through 8 weeks underaccelerated conditions of 40° C. and 75% relative humidity. In contrast,compositions 6, 7 and 10 all became discolored to some extent; and suchdiscoloration was observable after only two weeks under the acceleratedconditions.

Example 2: Stability Studies of Nasal Metoclopramide Compositions

Introduction and Background

An analytical testing method was developed to quantify discoloration offive metoclopramide hydrochloride nasal spray solutions employingguidelines in the United States Pharmacopeia (USP). See, 32 USP <631>,<1061> and <851>.

Preparation of Test Samples

Test samples were prepared having the formulations set forth in Table2-1, below, according to the following procedure. Water was purged withnitrogen gas for about 20 minutes and a gentle nitrogen sparge wasmaintained during preparation of the solution. About 50-60% of therequired amount of purified water was charged into a glass beakercontaining a Teflon® stir bar and wrapped with aluminum foil. Benzylalcohol and benzalkonium chloride were then added to the water andmixed. (In formulations F-1 and F-22, menthol was first added to benzylalcohol and mixed until visually dissolved; then the benzyl alcohol,menthol solution was added to the water.) Edetate disodium was added tothe solution and mixed until dissolved. Buffering ingredients (aceticacid/sodium acetate or citric acid/sodium citrate) were added insequence and mixed until dissolved. Metoclopramide hydrochloride wasthen added slowly to the solution and mixed until dissolved. Sorbitolwas then added and mixed until dissolved. The pH was then measured andrecorded. The pH was adjusted, if necessary, and the amount of bufferagent added was recorded. The solution in the mixing tank was thenbrought up to its final volume by adding previously-purged purifiedwater. The resulting solution was then filtered through a 10 μmcartridge filter. Filtered solution was then dispensed into clear glassvials, which were wrapped with aluminum foil. Representative sampleswere tested for potency (metoclopramide concentration) by a reversephase high performance liquid chromatography (RP-HPLC) method that hadbeen previously developed and validated.

TABLE 2-1 Composition of Five Metoclopramide Formulations Formulation (%w/v) Ingredient F-1 F-22 F-43 F-60 F-P Metoclopramide HCl, USP 23.64*23.64* 23.64* 23.64* 23.64* Glacial Acetic Acid, USP 0.32 0.057 0.057 —— Sodium Acetate trihydrate, USP 0.128 0.728 0.728 — — Citric Acidmonohydrate, USP — — — 0.10 0.10 Sodium Citrate dihydrate, USP — — —0.44 0.44 Benzyl Alcohol, NF 1.5 1.5 — 0.75 — Benzalkonium ChlorideSolution — — 0.025 — 0.025 50%, NF Sodium Chloride, USP 0.8 0.8 — — —Edatate Disodium, dehydrate, USP 0.1 0.1 0.1 0.1 0.1 Sorbitol Solution(70%), USP 6.424 6.424 3.00 — 3.00 Menthol Crystals, USP 0.08 0.08 — — —Purified Water, USP QS QS QS QS QS pH 3.90 5.5 ± 0.2 5.5 ± 0.2 5.5 ± 0.25.5 ± 0.2Analytical Method

Optical density (OD) was calculated according to the following formula:

${\%\mspace{14mu} O\; D} = \frac{{Absorbance}\mspace{14mu}{of}\mspace{14mu}{Sample} \times 100\%}{{Absorbance}\mspace{14mu}{of}\mspace{14mu}{Standard}}$

wherein:

Absorbance of Standard is the absorbance at 450 nm of 0.0005 M iodine inwater; and

Absorbance of Sample is the absorbance at 450 nm of a metoclopramidesample as described herein.

The OD was measured at 450 nm on the first day and after 1, 2, 4, and 8weeks of storage under normal conditions (25° C./60% RH) and acceleratedconditions (40° C./75% RH).

Five formulations containing about 200 mg/mL metoclopramide as free basewere assayed for drug potency and optical density. These data arepresented in Table 2-2. Each freshly prepared formulation demonstrated apale, light brownish color. The initial optical density of eachformulation was determined to be about 5-6%, as calibrated with respectto a 0.0005 M iodine solution at 450 nm.

TABLE 2-2 Potency assays and optical densities at 450 nm from bulk nasalspray solutions of metoclopramide hydrochloride ChromatographicFormulation No. % Label Claim Purity (% Peak Area) % O.D.  1 97.3 99.94.9 22 95.7 99.9 5.7 43 97.1 100.0 5.6 60 97.7 100.0 5.1 Production 96.5100.0 5.2

The color and clarity stabilities under the storage conditions undernormal conditions (25° C./60% RH) and accelerated conditions (40° C./75%RH) are presented as % optical densities in Tables 2-3a and 2-3b,respectively.

TABLE 2-3a Color and clarity stabilities of five metoclopramide nasalspray solutions at 25° C./60% RH Formulation No. T (0) T (1 wk) T (2 wk)T (4 wk) T (8 wk) % O.D. F-1  4.9 8.8 11.1 12.7 6.4 F-22 5.7 10.4 15.811.5 9.5 F-43 5.6 10.1 13.9 10.4 8.9 F-60 5.1 10.3 13.6 11.8 9.5 F-P 5.2 10.8 13.2 12.2 11.5 Absorbance F-1  0.01196 0.02147 0.02708 0.030990.01562 F-22 0.01391 0.02538 0.03855 0.02806 0.02318 F-43 0.013660.02464 0.03392 0.02538 0.02172 F-60 0.01244 0.02513 0.03318 0.028790.02318 F-P  0.01269 0.02635 0.03221 0.02977 0.02806

TABLE 2-3b Color and clarity stabilities of five metoclopramide nasalspray solutions at 40° C./75% RH Formulation % O.D. No. T (0) T (1 wk) T(2 wk) T (4 wk) T (8 wk) F-1  4.9 12.0 14.9 16.9 22.3 F-22 5.7 14.9 18.623.5 33.1 F-43 5.6 13.1 15.0 17.3 21.9 F-60 5.1 13.3 14.0 13.6 17.4 F-P 5.2 13.5 16.3 18.8 22.7 F-1  0.01196 0.02928 0.03636 0.04124 0.05441F-22 0.01391 0.03636 0.04538 0.05734 0.08076 F-43 0.01366 0.03196 0.03660.04221 0.05344 F-60 0.01244 0.03245 0.03416 0.03318 0.04246 F-P 0.01269 0.03294 0.03977 0.04587 0.05539

No significant change in optical density was observed from eachformulation under the storage conditions at 25° C./60% RH for 8 weeks.However, optical density increases were observed in all solutions testedat 40° C./75% RH for 8 weeks. Formulation F-22 demonstrated the mostlinear increase in optical density of all the formulations—about 2.5%per week between weeks 1 and 8.

Stability of pH

The pH of each formulation was also determined after 8 weeks at bothstorage conditions (25° C./60% RH and 40° C./75% RH) compared to theirinitial pH's, as shown in Table 2-4. All pH's at both storage conditionswere within ±0.2 pH units of the starting pH's.

TABLE 2-4 pH stabilities of five metoclopramide nasal spray solutionsafter 8 wee storage at 25° C./60% RH and 40° C./75% RH FormulationTarget pH pH at T (8 wks) No. pH at T (0) 25° C./60% RH 40° C./75% RHF-1  3.9 ± 0.2 3.80 3.76 3.67 F-22 5.5 ± 0.2 5.20 5.43 5.30 F-43 5.5 ±0.2 5.52 5.48 5.37 F-60 5.5 ± 0.2 5.40 5.26 5.24 F-P  5.5 ± 0.2 5.415.23 5.22

From the foregoing, it can be seen that formulation F-22 was the mostgreatly affected of all the tested samples.

Example 3: Stability Studies of Nasal Metoclopramide Compositions

Introduction and Background

An analytical testing method was developed to quantify discoloration offive metoclopramide hydrochloride nasal spray solutions employingguidelines in the United States Pharmacopeia (USP). See, 32 USP <631>,<1061> and <851>.

Preparation of Test Samples

A second set of samples (sample set #2) was prepared having theformulations set forth in Table 2-1, above, according to the procedureoutlined in Example 2, except that the samples were exposed to ambientair by puncturing the stoppers of the containers with needles, whichwere left in place during testing.

The OD was measured at 450 nm on the first day (T(0)) and after 4 (T(4wk)), and 8 (T(8 wk)) weeks, of storage under normal conditions (25°C./60% RH) and accelerated conditions (40° C./75% RH).

Five formulations (F-1, F-22, F-43, F-60 and F-P) containing about 200mg/mL metoclopramide as free base were assayed for optical density.These data are presented in Table 3-1. Each freshly prepared formulationdemonstrated a pale, light brownish color. The initial optical densityof each formulation was determined to be about 5-6%, as calibrated withrespect to a 0.0005 M iodine solution at 450 nm.

TABLE 3-1 Color and clarity stabilities of five metoclopramide nasalspray solutions at 40° C./75% RH Formulation No. T (0) T (4 wk) T (8 wk)F-1  6.1 11.9 15.7 F-22 7.9 17.8 26.5 F-43 7.6 10.9 13.0 F-60 7.0 13.910.4 F-P  7.1 15.7 15.9

Optical density increases were observed in all solutions tested at 40°C./75% RH for 8 weeks. Formulation F-22 demonstrated the most linearincrease in optical density of all the formulations.

A single formulation, prepared according to the description of F-P (200mg/mL of metoclopramide free base) was stored, 7.5. mL per vial, inamber glass vials for from 0 to 6 months at the conditions indicated inthe following Table 3-2. The color standard referenced in Table 3-2 isstandard “E” per 32 USP <631>, as referenced hereinabove.

TABLE 3-2 Stability of Metoclopramide 200 mg/mL solution (F-P) at 1, 3and 6 months. T-1 month T-3 months T-3 months T-6 months T-6 months T040° C./75% RH 25° C./60% RH 40° C./75% RH 25° C./60% RH 40° C./75% RHPale yellow Pale yellow Pale yellow Pale yellow Pale yellow Pale yellowsolution solution solution solution solution solution with color withcolor darker darker than standard than standard solution solution

As can be seen in Table 3-2, under normal conditions (25° C./60%Relative Humidity), the solution was colorless to pale yellow (same orlighter than 32 USP <631>“E” color standard) up to 6 months.Additionally, under accelerated conditions (40° C./75% RH), the solutionwas colorless to pale yellow (same or lighter than 32 USP <631>“E” colorstandard) at one month, but darker than the standard solution at 3 and 6months.

Example 4: Clinical Study of Nasally Administrable MetoclopramideComposition

Overall Study Design and Plan.

A multi-center, controlled, randomized, open-label, parallel designstudy in patients with diabetic gastroparesis is carried out. Eligiblepatients are randomized to receive metoclopramide nasal spray 10 mg,metoclopramide nasal spray 20 mg or oral metoclopramide 10 mg tablets inratio 2:2:1 four times daily before meals and at bedtime for six weeks.

Treatments to be Administered

Intranasal Medication: The metoclopramide 200 mg/ml solution is packagedwith a pump that delivers 0.05 ml per spray for the 10 mg strength orwith a pump that delivers 0.1 ml per spray for the 20 mg strength.Patients randomized to receive metoclopramide nasal spray 10 mg or 20 mgreceived one spray per dose. The formulation is one of the formulationsset forth in Example 1, above.

Randomized Treatment or Crossover Phase

Patients who are determined eligible for inclusion in the studyfollowing the screening visit are block-randomized within each center ina 2:2:1 ratio (metoclopramide nasal spray 10 mg, metoclopramide nasalspray 20 mg and oral metoclopramide 10 mg respectively) with a blocksize of 5.

Selection and Timing of Dose for Each Patient

All patients randomized to nasal spray are instructed to do thefollowing: actuates the nasal spray device once into one nostril, fourtimes daily, before meals and at bedtime; alternates nostrils with eachapplication.

Patients randomized to oral metoclopramide tablets are instructed totake one tablet four times daily, 30 minutes before meals and atbedtime.

If the patient misses a meal, he/she is instructed to still takemedication as scheduled. If the patient eats more than three meals inone day, he/she is instructed to not take additional medication. If adose of medication is forgotten, he/she is advised to take it as soon ashe/she remembers. Doses greater than 2 hours late are omitted. Thepatients are instructed not to take a double dose of the medication atthe next scheduled time if a dose is missed.

Patients will begin taking the medication on study Day 1 and completethe study on Day 42.

Symptom Assessment

A symptom assessment tool, modified from the tool described by Perkeland colleagues (M. S. Perkel, T. Hersh, C. Moore, E. D. Davidson,“Metoclopramide Therapy in Fifty-five Patients With Delayed GastricEmptying”; Am J Gastroenterol 1980; 74:231-236, which is incorporatedherein in its entirety), is used to assess symptoms and therapeuticefficacy before, during, and at the conclusion of treatment. Themodifications to the Perkel scale includes removal of items which areredundant or are not considered hallmark symptoms of gastroparesis.Simple language changes (medical to layman terminology) and more preciseresponse specifications are also includes to increase inter-siteconsistency and are self-reported on the Symptom AssessmentQuestionnaire (“SAQ”). Patients are asked to rate the frequency of eachof six target symptoms during the week prior to the assessment. Thetarget symptoms are nausea, vomiting, anorexia, bloating, early satietyand meal tolerance. Patients assign each symptom a predefined ordinalfrequency score of zero to four.

Also included is an assessment of severity in the evaluation of diabeticgastroparesis symptoms (W. S. Longo, A. M. Vernava; “Prokinetic Agentsfor Lower Gastrointestinal Motility Disorders”, Dis Colon Rectum 1993;36:696-708, incorporated by reference in its entirety). AnInvestigator's Assessment Questionnaire (“IAQ”) is includes to assessthe severity of the symptoms and therapeutic efficacy before, during,and at the conclusion of treatment following speaking to the patient.

A total symptom score is calculated as the sum of the ratings of the SAQand IAQ.

Entry criteria for the study includes a total score of between 8 and 20on each of the SAQ and IAQ, based upon a moderate or greater grading ofat least two symptoms and varying grading on other symptoms. Patientswith a score higher than 40 are excluded. On each of the scales (SAQ andIAQ), a minimum of two out of six symptoms must have been rated moderate(2) or higher.

Efficacy Parameters

Efficacy measurements include the patient's SAQ and IAQ scores. Bothquestionnaires are completed at baseline and once per week during the 6week treatment period: Days 7, 14, 21, 28, 35 and 42, respectively.

The SAQ and IAQ each have 6 symptom items, including nausea, vomiting,loss of appetite, feeling bloeatsd, feeling full after eating a smallamount of food, and persistent fullness after eating. The SAQ assessesthe frequency of the symptoms, whereas the IAQ examines the severity.The SAQ is completed first since the physician needs to discuss thesymptoms with the patient prior to the completion of the IAQ.

Primary Efficacy Parameter

The primary efficacy endpoint is the change from the baseline to the endof the study in the total symptom score. The total symptom score is thesum of the six patient-rated frequency items plus the sum of the sixinvestigator-rated severity items. If a patient terminates prematurelyfrom the study, the last available total symptom assessment score isused.

Secondary Efficacy Parameter

The secondary efficacy endpoints involved both changes from baseline inthe weekly total symptom scores and combined severity and frequencyscore (severity score plus frequency score) for each individual symptom.Each combined item has a possible score of 0 to 8.

RESULTS

Efficacy Analysis

The primary efficacy endpoint for the study is the change in totalsymptom score between baseline and week 6. The primary analysis ofefficacy is an intent-to-treat analysis where all patients who arerandomized to one of the three treatments and have at least onepost-randomization assessment (including SAQ and IAQ) are includes.

The secondary analysis of efficacy is a “per protocol” analysis whichincludes all patients who completed the study per protocol. This perprotocol analysis is performed only for the primary efficacy endpoint,i.e., the change from baseline to the end of the study in the totalsymptom score. Patients who do not meet the baseline SAQ/IAQ scorecriteria are excluded. The SAQ and IAQ taken during the time interval inwhich prohibited concomitant therapies are taken are also excluded fromthe per protocol analysis.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A method of treating gastroparesis in a patient,comprising intranasally administering to the patient an amount of ametoclopramide composition effective to deliver about 15 mg ofmetoclopramide, or a pharmaceutically-acceptable salt thereof, to thepatient, wherein the composition comprises citrate in a concentration ofat least about 10 millimolar, and wherein the intranasally administeringis effective to treat gastroparesis.
 2. The method of claim 1, whereinthe metoclopramide composition further comprises a buffer.
 3. The methodof claim 1, wherein the metoclopramide composition further comprisesbenzalkonium chloride.
 4. The method of claim 3, wherein themetoclopramide composition has a concentration of benzalkonium chloridefrom about 0.005% (w/v) to about 0.05% (w/v).
 5. The method of claim 1,wherein the metoclopramide composition has a pH of above about 4.5. 6.The method of claim 1, wherein the metoclopramide composition furthercomprises benzyl alcohol.
 7. The method of claim 1, wherein themetoclopramide composition has an osmolality of from about 500 mOsm/kgto about 1400 mOsm/kg.
 8. The method of claim 2, wherein the buffer isselected from the group consisting of citric acid/phosphate, acetate,barbital, borate, Britton-Robinson, cacodylate, citrate, collidine,formate, maleate, McIlvaine, phosphate, Prideaux-Ward, succinate,citrate-phosphate-borate (Teorell-Stanhagen), veronal acetate, IVIES(2-(N-morpholino)ethanesulfonic acid), BIS-TRIS(bis(2-hydroxyethyl)iminotris(hydroxymethyl)methane), ADA(N-(2-acetamido)-2-iminodiacetic acid), ACES(N-(carbamoylmethyl)-2-aminoethanesulfonaic acid), PIPES(piperazine-N,N′-bis(2-ethanesulfonic acid)), MOPSO(3-(N-morpholino)-2-hydroxypropanesulfonic acid), BIS-TRIS PROPANE(1,3-bis(tris(hydroxymethyl)methylamino)propane), BES(N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonaic acid), MOPS(3-(N-morpholino)propanesulfonic acid), TES(N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid), HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), DIPSO(3-(N,N-bis(2-hydroxyethyl)amino)-2-hydroxypropanesulfonic acid), MOBS(4-(N-morpholino)butanesulfonic acid), TAPSO(3-(N-tris(hydroxymethyl)methylamino)-2-hydroxy-propanesulfonic acid),tris(hydroxymethylaminomethane,HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonic acid),POPSO (piperazine-N,N′-bis(2-hydroxypropanesulfonic acid)), TEA(triethanolamine),EPPS(N-(2-hydroxyethyl)piperazine-N′-(3-propane-sulfonic acid), TWINE(N-tris(hydroxymethyl)methylglycine), GLY-GLY (glycylglycine), BICINE(N,N-bis(2-hydroxyethyl)glycine), HEPBS(N-(2-hydroxyethyl)piperazine-N′-(4-butanesulfonic acid)),TAPS(N-tris(hydroxy-methypmethyl-3-aminopropanesulfonic acid), or AMPD(2-amino-2-methyl-1,3-propanediol) buffer.
 9. The method of claim 8,wherein the buffer comprises sodium acetate.
 10. The method of claim 8,wherein the buffer comprises sodium citrate.
 11. The method of claim 1,wherein the patient has a disorder that is treatable withmetoclopramide.
 12. The method of claim 9, wherein the disorder that istreatable with metoclopramide is selected from the group consisting ofgastroparesis, emesis, delayed emesis, and nausea.
 13. The method ofclaim 6, wherein the metoclopramide composition has a benzyl alcoholconcentration from about 0.01% (w/v) to about 0.8% (w/v).
 14. The methodof claim 1, wherein the metoclopramide composition further comprises atleast one member of the group consisting of a salt, EDTA, sorbitol, asugar, or a flavoring agent.
 15. The method of claim 1, wherein theintranasal administration comprises an intranasal spray.
 16. The methodof claim 15, wherein the intranasal spray is administered as two sprays.17. The method of claim 1, wherein the patient is human.